All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Quinones of various chemical families, present in plants and animals, serve as biological modulators [Routledge et al. (1996) Naturally Occurring Quinones, Kluwer Academic Publishers; Stites et al. (2002) Journal of Nutrition 132, 719-727; Lee, K. H. (1999) Medicinal Research Reviews 19, 569-596; Thomson, R. H. (1987) Naturally Occurring Quinones, Routledge, Chapman & Hall, Incorporated; Bolton et al. (2000) Chemical Research in Toxicology 13, 135-160] and both natural and synthetic quinones are widely used as drugs. Anthracyclines, a large group of quinonoid compounds produced by different strains of Streptomyces, exert antibiotic and antineoplasic effects and are used to treat some forms of cancer [Begleiter, A. (2000) Frontiers in Bioscience 5, E153-E171; Aubel-Sadron, G. and Landos-Gagliardi, D. (1984) Biochimie 66, 333-352]. The best known members of this family are daunorubicin and doxorubicin, the first identified anthracyclins [Di Marco et al. (1981) Cancer Treat Rep 65, 3-8]. Other quinones are also used as anticancer drugs. Mitomycin C and streptonigrin produced by Streptomyces and the synthetic epirubicin and mitoxantron are well known examples. Although these and other quinonoid compounds are effective in the treatment of many different forms of cancer, their side effects—the most severe of them being cumulative heart toxicity—limit their use. Thus, development of quinonoid compounds that display antineoplastic activity, but are less toxic, is a major therapeutic goal [Zucchi, R., Danesi, R. (2003) Curr Med Chem Anti-Canc Agents 3, 151-171; Thomas, X. et al. (2002) Ann Hemathol 81, 504-507].
A large number of cannabinoids have been synthesized and tested in the in vitro and in vivo models of various diseases [Razdan, R. K. (1986) Pharmacol Rev. 38, 75-149; Mechoulam, et al. (1998) Progress in Med Chem 35, 199-243; Barth, F., Rinaldi-Carmona, M. (1999) Curr Med Chem. 6, 745-55]. In the present study, five cannabinoic quinones, two of which were originally prepared by the inventors to investigate the chemical basis of the Beam test (a color test for cannabinoids) [Mechoulam, R. et al. (1968) Tetrahedron 24, 5615-5624], and three novel cannabinoic quinones which are disclosed herein, were evaluated as medicinal agents. In particular, the present inventors wished to find cannabinoic quinones which would present biological and therapeutic activity, with minimized side effects, a major problem usually found in these compounds.
The present report encompasses the medicinal properties of these quinone cannabinoid derivatives, especially with regards to their potent antineoplastic activity both in vitro and in vivo, with no measurable side-effects.
Thus, it is an object of the present invention to provide pharmaceutical compositions comprising cannabinoic quinones as the active agent. It is a further object to provide said compounds as anti-neoplastic or anti-cancer drugs. Other uses and objects of the invention will become clear as the description proceeds.